Volunteer subjects with previous histories of cocaine use were administered cocaine hydrochloride intravenously or intranasally. There was a positive relationship between peak plasma concentration, physiological and subjective responses, and dose administered. The rate of cocaine disappearance after intravenous administration paralleled the drop in physiological and subjective drug effects. After intranasal administration, blood levels remained elevated for a considerably longer period.
We conclude that high-dose cocaine possesses negative inotropic and potent type I electrophysiological effects. Sodium bicarbonate selectively reversed cocaine-induced QRS prolongation and may be a useful treatment of ventricular arrhythmias associated with slowed ventricular conduction in the setting of cocaine overdose.
Cocaine kinetics were studied in four subjects after intravenous and intranasal administration. For intravenous administration cocaine hydrochloride (32 mg) dissolved in physiological saline was injected in 1 ml volume over a 1 min period. Intranasal cocaine was administered as 100 mg powder consisting of an appropriate dose of cocaine hydrochloride (64 and 96 mg) mixed with lactose powder. Subjects were instructed to inhale the mixture through a 5 cm straw within 1 min. Cocaine kinetics, after intravenous injection, conform to a one-compartment open model with first-order elimination. After intranasal administration, cocaine kinetics conform to a one-compartment model with first-order absorption and first-order elimination. The mean half-life of cocaine for intravenous injection in four subjects was 41.4 +/- 8.2 min (mean +/- S.E.M.) and the range was 19 to 64 min. There were statistically significant differences in the mean area under the concentration-time curve (AUC) following intravenous and intranasal administration. The AUC was dose-dependent and the fraction of the dose absorbed after 64 mg intranasal cocaine was significantly lower than after 96 mg dose (p less than 0.05).
The antipsychotics are a chemically diverse group of heterocyclic compounds, which ameliorate many symptoms of schizophrenia. Most of the antipsychotics are very lipophilic and cross lipoidal membranes freely. When administered orally, they are well absorbed and undergo substantial pre-systemic elimination (bioavailability: 10-70%), are highly bound to plasma proteins (75-99%) and tissues, and are extensively distributed (VD: 100-1000 L). Primary route of elimination for most of antipsychotics is hepatic metabolism and biotransformation produces active metabolites. There is no linear relationship between the concentration of parent compound and different metabolites, and clinical relevance of pharmacologically active metabolites is not well understood. There are wide interindividual variabilities in pharmacokinetics, which result in large differences in steady-state plasma concentrations on the same dose regimen. The existence of optimal therapeutic ranges for most antipsychotics remains controversial. One of the major problems is the lack of well-designed studies that involve sufficient numbers of patients to clearly establish a therapeutic range for these drugs and is further complicated by the presence of a large number of pharmacologically active metabolites. However, the pronounced interindividual kinetic variabilities, combined with problems of noncompliance and drug interactions, and the delayed onset of clinical response in relation to initiation of treatment with antipsychotics are reasons why drug monitoring in conjunction with clinical status of the patient can be useful. Indications for antipsychotic drug monitoring include lack of response, non-compliance, toxicity, and drug interactions when other drugs are coadministered.
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